Bioprosthetic components that are based on a native or possibly modified biological material or that comprise biological materials as a component are also increasingly considered for implants in the prior art. The surface of the biological material that is to be used as a bioprosthetic component for an implant is normally subjected to a stabilizing treatment before use. Common examples for the use of such implants include, for example, various heart valves, such as heart leaflets, aortic valves, mitral valves and pulmonary valves. Further examples for the use of such implants include, for example, venous valves and what are known as “closure devices”, such as aneurysm stents, which can be used throughout the blood circulation system, including in the region of the brain, as well as heart leaflets for sealing scarring that may have been caused for example by an operation on the heart, for example the correction of a genetically caused opening between chambers of the heart. The opening between chambers of the heart caused by a gene defect, which may often require treatment as early as childhood, may be an atrioventricular septal defect, an atrial septal defect or a ventricular septal defect for example.
In mammals, the heart is the organ responsible for maintaining an adequate supply by pumping blood throughout the body so that all parts of the body are supplied sufficiently with oxygen and nutrients. The back-flow of blood into the heart is prevented by four valves (heart valves), which are used as an inlet and outlet for each of the two chambers of the heart, which serve as pump chambers of the heart.
Incorrect functioning of one or more of these valves may have serious implications for health. Such incorrect functioning may be caused by deformations from birth or by damage caused by disease. Forms of incorrect functioning include stenosis (a narrowing in the mouth of the open valve) and the back-flow of blood through the closure or through the closed valve, wherein both situations require increased performance of the heart to maintain the corresponding blood flow in the body. In many cases, the only effective solution lies in replacing the incorrectly functioning valve.
The use of artificial heart valves unfortunately requires life-long treatment with anticoagulants for patients, since blood clots may otherwise form on the valve mechanism of the artificial heart valve. Blood clots on the valve mechanism may limit the movability of the parts of the valve aperture, may impair valve function or may detach from the valve mechanism and close the blood vessels behind the valve. In the case of mechanical valves, the closure element rotates in the flow-through opening, but is not moved away from the flow-through opening when the valve opens. This limits the flow of blood, but, more importantly, it disturbs the blood flow patterns. This disturbance of the blood flow is generally considered to be a cause of, or at least a significant contribution to, the observed tendency of mechanical valves to cause blood clotting.
Biological prostheses, for example biological replacement heart valves, that are obtained from natural tissues may be preferred due to specific clinical advantages compared to mechanical devices. For example, in tissue-based prostheses the routine anticoagulation is generally not necessary and, whereas mechanical prostheses may typically fail suddenly, there is conversely generally initially a gradual worsening with tissue-based prostheses, which can last for a period of months or even years and therefore provides an early indication of a possible failure. Besides artificial heart valves, biological heart valves are therefore also used as a replacement for incorrectly functioning heart valves in specific patient groups, for example in which the implantation of artificial heart valves is rejected.
Although the likelihood of blood clotting with biological heart valves is much lower compared to mechanical replacement valves, and patients with biological heart valves therefore generally do not have to be treated with anticoagulants, with the exception of the immediate post-operative period, the known biological heart valves still also require improvement. Biological heart valves can degenerate over time, often as a result of mineralization or calcification of the crosslinked natural tissue, which poses a serious problem in young patients in particular. Although receivers of a biological heart valve therefore do not have to take anticoagulants, such as Marcumar, the service life of biological heart valves is much shorter than that of mechanical valves.
Although any prosthetic valve may fail as a result of mineralization, such as calcification, this problem of gradual prosthesis degeneration is of particular clinical significance in the case of bioprosthetic heart valves obtained from tissue. The pathogenesis of the calcification is not fully known, and, in addition, even today there is still the lack of a sufficiently effective therapy.
Possible causes will be described briefly, without favoring or being tied to a specific theory. For example, with regard to the source of mineralization and of calcification in particular, it has been proven that these start primarily with cell debris, which occurs in tissue matrices of bioprosthetic heart valves, more specifically equally in bioprosthetic heart valves originating from pericardium or aortic root. The calcification of bioprosthetic crosslinked tissue has also been linked to the presence of alkaline phosphatases in cell debris and the possible accumulation thereof within the implanted tissue from the blood. Mineralization could also be caused by the fact that phospholipids in the cell debris sequester calcium and form the nucleation point of apatite (calcium phosphate). It has also bee proposed that sub-units of elastin and fibrillin may be a cause of calcification due to the calcium-binding function of these proteins. Irrespective of its mechanism, mineralization in bioprostheses, and calcification in particular, is considered to be the most common cause of the clinical failure of bioprosthetic heart valves obtained from porcine aortic valves or bovine pericardium. In the case of human aortic homograft implants, pathological calcification has likewise been observed, although in this case it occurs more slowly than with bioprosthetic heart valves, but affects both the valve tissue and also the adjacent aortic wall. Pathological calcification ultimately leads to failure of the valve, for example in the form of stenosis and/or regeneration, and requires re-implantation. Since bioprosthetic heart valves and also homograft heart valves are subject to calcification, the clinical use thereof is now limited, in spite of some solution approaches to reduce or prevent mineralization or calcification.
A number of methods for reducing mineralization and calcification in bioprosthetic heart valves to the greatest possible extent or for eliminating these processes have been applied in the prior art. In these methods, the bioprosthetic heart valves are normally treated with various substances before implantation. Suitable substances that have been described include sulfated aliphatic alcohols, phosphate esters, amino acids, diphosphonates, derivatives of carboxylic acids and various surfactants. Another method uses amino oleic acid (AOA) as a means for alleviating calcification in bioprosthetic heart valves made of porcine aortic root tissue. Effective prevention of mineralization of the aortic wall could not previously be achieved by application of these methods however, and a successful solution to the problem of the occurrence of mineralization after implantation is still yet to be developed.
Furthermore, bioprostheses made of animal tissue, for example porcine heart valves, trigger immunogenic and inflammatory reactions of varying severity in receivers. It is therefore attempted generally, and in the case of the present invention too, to prevent an immunological rejection by means of chemical treatment of the animal tissue. The current method of glutaraldehyde fixing can indeed considerably mask the antigenicity of an implanted porcine valve tissue, but cannot overcome it completely. Even porcine heart valves may therefore still lead, after glutaraldehyde fixing, to a slight to severe inflammatory reaction, which can be attributed in part to the cytotoxic nature of glutaraldehyde, and in more severe cases the foreign tissue may even cause a chronic inflammatory reaction.
Reference is made to patent publications U.S. Pat. No. 6,166,184 (Methods for making bioprosthetic devices) and U.S. Pat. No. 6,509,145 (Process for reducing mineralization of tissue used in transplantation), and to published US patent applications U.S. Pat. No. 7,078,163, US 2003/0118981 A1 (Process for reducing mineralization of tissue used in transplantation), WO 2005/011764, US 2005/0020506 A1 (Crosslinked compositions comprising collagen and demineralized bone matrix, methods of making and methods of use) as exemplary methods for treating tissues before transplantation, the aforesaid documents describing methods for treating biological tissue before implantation.
Previously, the biological heart valves, for example the heart valve leaflets, were also decellularized. “Decellularization” is understood to mean a method for removing cells and cell debris from tissue and tissue structures. This decellurization is generally applied in the case of bioprosthetic heart valves produced from porcine aortic valves or bovine pericardium.
US 2005/0266390 A1 thus describes a method for decellurization of mammalian tissue for use in transplant medicine and tissue engineering. In this method an ionic detergent and a non-ionic detergent are applied simultaneously to mammalian tissue over a relatively long period of time, which may last for more than five days. In this case, SDS for example is used as an ionic detergent and Triton X-100 is used as a non-ionic detergent. A considerable rinsing step follows, which likewise may last for more than five days. This extraction with subsequent rinsing is supposed to deliver a tissue with stress-strain curves and DSC data similar to that of fresh, unprocessed tissues. US 2005/0266390 A1 also discloses the fact that the processed tissue is free from cells for the most part and that the underlying structure remains substantially intact and demonstrates much improved behavior with regard to inflammatory reactions relative to fresh tissue, even without glutaraldehyde fixing, as well as a much lower level of calcification in situ based on glutaraldehyde-fixed tissue. For example, the method can be used for the decellurization of porcine heart valve leaflets and porcine heart wall tissue before use in transplantation.
WO 2005/118014 also describes a method for decellurization for tissue that is to be used as a bioprosthetic replacement in transplantations. The method of WO 2005/118014 concerns the treatment of tissue that still contains cell membranes and is cut from an animal for the production of a tissue-based implantable bioprosthesis. In this method the cut tissue is contacted simultaneously with two different detergents, wherein one is an ionic detergent that can destroy cell membranes, and the other is a detergent having a neutral net charge.
However, decellurization leads to a material that has inadequate mechanical properties. So as to improve the mechanical properties of the material, the entire material is chemically crosslinked in the prior art and is thus mechanically improved, that is to say as a result of treatment of the entire surface and of the underlying layers. Chemical crosslinking involves risks, however. Groups that have not abreacted have to be removed, which is costly, so as to ensure a sufficient biocompatibility of the material. Examples of these efforts made in the prior art to again remove crosslinking reagents such as glutaraldehyde include the “ThermaFix” method (Edwards) or the “AOA Tissue Treatment” method (Medtronic). In the case of “AOA Tissue Treatment” for example, this involves the above-mentioned treatment of the tissue using amino oleic acid (AOA).
The “ThermaFix” process involves a treatment of the tissue that is effective against lime deposits. Glutaraldehyde fixing is merely the first step of the tissue treatment in this instance (Southern L J, et al. Glutaraldehyde—indeed cross-links: a study of model compounds and commercial bioprosthetic valves. J Heart Valve Dis 2000; 9 (2):241-8). Glutaraldehyde fixing assists tissue conversion and sterility and improves biocompatibility and structural stability. If, with the tissue treatments in the prior art, calcium deposit sites such as phospholipids and unstable glutaraldehyde radical molecules are merely chemically bonded, the effect against lime deposition may decrease over time. Compared to chemical bonding (fixing) alone, a further improvement can be achieved by subsequent extraction. With the enhanced “ThermaFix” tissue method, the calcium deposit sites such as phospholipids and unstable glutaraldehyde radical molecules are therefore additionally extracted.
The prior art methods have the disadvantage that the entire surface of the biological material is chemically altered, possibly including the underlying layers in part or completely, although in practice tears and a failure of the structure occur predominantly at the edges of the biological material. In addition, the biological material is made stiffer on the whole as a result of the treatment of the entire heart valve, and this leads to a homogeneous material over the entire heart valve. This contradicts the locally different requirements of the heart valve. For example, the edge regions are subject to different stresses at the stitching points compared to at the edge regions in the lumen, wherein the requirements in the central region of the heart valve are in turn quite different.
In the prior art there is therefore still a considerable need, for implants, to improve the properties of bioprosthetic components that are based on, or comprise, biological materials, particularly in view of mechanical stability, service life and biocompatibility for example. In this case, there is a specific need to improve the properties of biological heart valves inter alia, in particular of biological heart valve leaflets, for use thereof as implants.
There is thus still a considerable demand for an improved bioprosthetic or biological heart valve replacement having good hemodynamic performance, a long service life, and/or improved biocompatibility, for example with a sufficient reduction in the risk of the induction of blood clotting so that the use of anticoagulants after implantation can be omitted, and/or a minimal risk of mineralization and/or calcification. There is also a need for other improved, permanent and non-immunogenic or only slightly immunogenic bioprosthetic tissues that are also compatible for patients in terms of healing and growth.
There is accordingly also a need for the provision of bioprosthetic (biological) heart valves and/or other implants (bioprosthetic materials), obtained from (homogeneous or xenogeneic) tissues, having improved biocompatibility, for example those that resist pathological calcification in the long term in vivo, and wherein the bioprosthetic (biological) implants, in particular heart valves, preferably also have improved long-term mechanical stability or ability to withstand continuous stressing. There is also a need for methods with which bioprosthetic (homogeneous or xenogeneic) tissue (or implants based thereon) having improved biocompatibility, for example that having reduced inflammatory and immune response, can be provided and with which bioprosthetic (homogeneous or xenogeneic) tissue in particular (or implants based thereon) having improved long-term mechanical stability or ability to withstand continuous stressing can also be produced.